Indoles and 1-(3-(benzyloxy)benzyl)piperazines: Reversible and selective monoamine oxidase B inhibitors identified by screening an in-house compound library.

The therapeutic indications for monoamine oxidases A and B (MAO-A and MAO-B) inhibitors that have emerged from biological studies on animal and cellular models of neurological and oncological diseases have focused drug discovery projects upon identifying reversible MAO inhibitors. Screening of our in-house academic compound library identified two hit compounds that inhibit MAO-B with IC50 values in micromolar range. Two series of indole (23 analogues) and 3-(benzyloxy)benzyl)piperazine (16 analogues) MAO-B inhibitors were derived from hits, and screened for their structure-activity relationships. Both series yielded low micromolar selective inhibitors of human MAO-B, namely indole 2 (IC50 = 12.63 ± 1.21 µM) and piperazine 39 (IC50 = 19.25 ± 4.89 µM), which is comparable to selective MAO-B inhibitor isatin (IC50 = 6.10 ± 2.81 µM), yet less potent in comparison to safinamide (IC50 = 0.029 ± 0.002 µM). Selective MAO-B inhibitors 2, 14, 38 and 39 exhibited favourable permeation of the blood-brain barrier and low cytotoxicity in the human neuroblastoma cell line SH-SY5Y.

A Tumor-Targeting Near-Infrared Heptamethine Cyanine Photosensitizer with Twisted Molecular Structure for Enhanced Imaging-Guided Cancer Phototherapy.

In recent years, cancer phototherapy has been extensively studied as noninvasive cancer treatment. To present efficient recognition toward cancer cells, most photosensitizers (PSs) are required to couple with tumor-targeted ligands. Interestingly, the heptamethine cyanine IR780 displays an intrinsic tumor-targeted feature even without modification. However, the photothermal efficacy and photostability of IR780 are not sufficient enough for clinical use. Herein, we involve a twisted structure of tetraphenylethene (TPE) between two molecules of IR780 to improve the photothermal conversion efficiency (PCE). The obtained molecule T780T shows strong near-infrared (NIR) fluorescence and improved PCE (38.5%) in the dispersed state. Also, the photothermal stability and ROS generation capability of T780T at the NIR range (808 nm) are both promoted. In the aqueous phase, the T780T was formulated into uniform nanoaggregates (∼200 nm) with extremely low fluorescence and PTT response, which would reduce in vivo imaging background and side effect of PTT response in normal tissues. After intravenous injection into tumor-bearing mice, the T780T nanoaggregates display high tumor accumulation and thus remarkably inhibit the tumor growth. Moreover, the enhanced photostability of the T780T allows for twice irradiation after one injection and leads to more significant tumor inhibition. In summary, our study presents a tumor-targeted small-molecule PS for efficient cancer therapy and brings a new design of heptamethine cyanine PS for potential clinical applications.

Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives Against Gram-Negative Multidrug-Resistant Pathogens.

Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido[4,5-b]indole derivatives represented by GP-1 demonstrated excellent broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria but were limited by hERG inhibition and poor pharmacokinetics profile. To improve their drug-like properties, we designed a series of novel pyrimido[4,5-b]indole derivatives based on the tricyclic scaffold of GP-1 and the C-7 moiety of acorafloxacin. These efforts have culminated in the discovery of a promising compound 18r with reduced hERG liability and an improved PK profile. Compound 18r exhibited superior broad-spectrum in vitro antibacterial activity compared to GP-1, including a variety of clinical multidrug G- pathogens, especially Acinetobacter baumannii, and the in vivo efficacy was also demonstrated in a neutropenic mouse thigh model of infection with multidrug-resistant A. baumannii.

Identification of new 3-phenyl-1H-indole-2-carbohydrazide derivatives and their structure-activity relationships as potent tubulin inhibitors and anticancer agents: A combined in silico, in vitro and synthetic study.

Virtual screening of commercially available molecular entities by using CDRUG, structure-based virtual screening, and similarity identified eight new derivatives of 3-phenyl-1H-indole-2-carbohydrazide with anti-proliferative activities. The molecules were tested experimentally for inhibition of tubulin polymerisation, which revealed furan-3-ylmethylene-3-phenyl-1H-indole-2-carbohydrazide (27a) as the most potent candidate. Molecule 27a was able to induce G2/M phase arrest in A549 cell line, similar to other tubulin inhibitors. Synthetic modifications of 27a were focussed on small substitutions on the furan ring, halogenation at R1 position and alteration of furyl connectivity. Derivatives 27b, 27d and 27i exhibited the strongest tubulin inhibition activities and were comparable to 27a. Bromine substitution at R1 position showed most prominent anticancer activities; derivatives 27b-27d displayed the strongest activities against HuCCA-1 cell line and were more potent than doxorubicin and the parent molecule 27a with IC50 values <0.5 µM. Notably, 27b with a 5-methoxy substitution on furan displayed the strongest activity against HepG2 cell line (IC50 = 0.34 µM), while 27d displayed stronger activity against A549 cell line (IC50 = 0.43 µM) compared to doxorubicin and 27a. Fluorine substitutions at the R1 position tended to show more modest anti-tubulin and anticancer activities, and change of 2-furyl to 3-furyl was tolerable. The new derivatives, thiophenyl 26, displayed the strongest activity against A549 cell line (IC50 = 0.19 µM), while 1-phenylethylidene 21b and 21c exhibited more modest anticancer activities with unclear mechanisms of action; 26 and 21c demonstrated G2/M phase arrest, but showed weak tubulin inhibitory properties. Molecular docking suggests the series inhibit tubulin at the colchicine site, in agreement with the experimental findings. The calculated molecular descriptors indicated that the molecules obey Lipinski's rule which suggests the molecules are drug-like structures.

Novel pH-Triggered Doxorubicin-Releasing Nanoparticles Self-Assembled by Functionalized ß-Cyclodextrin and Amphiphilic Phthalocyanine for Anticancer Therapy.

Cyclodextrins (CDs), as pharmaceutical excipients with excellent biocompatibility, non-immunogenicity, and low toxicity in vivo, are widely used to carry drugs by forming inclusion complexes for improving the solubility and stability of drugs. However, the limited space of CDs' lipophilic central cavity affects the loading of many drugs, especially with larger molecules. In this study, ß-CDs were modified by acetonization to improve the affinity for the chemotherapy drug doxorubicin (DOX), and doxorubicin-adsorbing acetalated ß-CDs (Ac-CD:DOX) self-assembled to nanoparticles, followed by coating with the amphiphilic zinc phthalocyanine photosensitizer ZnPc-(PEG)5 for antitumor therapy. The final product ZnPc-(PEG)5:Ac-CD:DOX was demonstrated to have excellent stability and pH-sensitive drug release characteristics. The cell viability and apoptosis assay showed synergistic cytotoxic effects of chemotherapy and phototherapy. The mechanism of cytotoxicity was analyzed in terms of intracellular reactive oxygen species, mitochondrial membrane potential, and subcellular localization. More importantly, in vivo experiments indicated that ZnPc-(PEG)5:Ac-CD:DOX possessed significant tumor targeting, prominent antitumor activity, and less side effects. Our strategy expands the application of CDs as drug carriers and provides new insights into the development of CD chemistry.

Porphyrin and phthalocyanine photosensitizers designed for targeted photodynamic therapy of colorectal cancer.

Colorectal cancer is of particular concern due to its high mortality rate count. Recent investigations on targeted phototherapy involving novel photosensitizers and drug-delivery systems have provided promising results and realistic prospects for a successful medical treatment. New research trends have been focused particularly on development of advanced molecular systems offering effective photoactive species which could be selectively delivered directly into the affected cells. Porphyrins and phthalocyanines have been considered extremely attractive for this purpose due to their molecular versatility, excellent photochemical properties and multifunctional nature. In this review it has been demonstrated that such macrocyclic compounds may effectively contribute to the inhibition of the growth of colon cancer cells and eventually to their photonecrosis. Purposely designed and tailored porphyrin and phthalocyanine derivatives in combination with smart drug-carriers have proved suitable for photodynamic therapy (PDT) and related antitumor treatments. This survey comprises a choice of potentially applicable ideas developed since 2010 involving 9 different tumor cell lines and featuring 32 photosensitizers.

New indole-7-aldehyde derivatives as melatonin analogues; synthesis and screening their antioxidant and anticancer potential.

Over the last decade, there has been substantial interest in the use of melatonin (MLT) and MLT-like compounds in the treatment of several diseases. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. Our ongoing study relies on changing the groups in the different modifiable sites of the indole ring to increase the antioxidant activity. In this study a new approach for substitution of indole ring as indole based MLT analogue was proposed. We report the synthesis and characterization of a series of new indole-7-aldehyde hydrazide/hydrazone derivatives as indole-based MLT analogues. Anticancer potential of the compounds were evaluated both by their antioxidant and CYP1 inhibitory activities. In vitro antioxidant capacity of the compounds was investigated both in a cell-based (DCFH assay) and a cell-free (DPPH assay) assay. Potential inhibitory effects of the compounds on CYP1 catalytic activity were investigated via EROD assay. Cytotoxic activity of the compounds was further evaluated by the MTT assay in CHO-K1 cells. MLT analogues having an o-halogenated aromatic moiety exhibited effective antioxidant properties without having any cytotoxic effect. In conclusion, MLT derivatives represent promising scaffolds for discovery of effective antioxidant agents.

Synthesis and evaluation of heterocycle structures as potential inhibitors of Mycobacterium tuberculosis UGM.

In this study, we screen three heterocyclic structures as potential inhibitors of UDP-galactopyranose mutase (UGM), an enzyme involved in the biosynthesis of the cell wall of Mycobacterium tuberculosis. In order to understand the binding mode, docking simulations are performed on the best inhibitors. Their activity on Mycobacterium tuberculosis is also evaluated. This study made it possible to highlight an "oxazepino-indole" structure as a new inhibitor of UGM and of M. tuberculosis growth in vitro.

Indole chalcones: Design, synthesis, in vitro and in silico evaluation against Mycobacterium tuberculosis.

Indole chalcones were designed and synthesized as a promising set of compounds against H37Rv strain of Mycobacterium tuberculosis. Within this library of compounds, (E)-1-(furan-3-yl)-3-(1H-indol-3-yl)prop-2-en-1-one (18), (E)-3-(1H-indol-3-yl)-1-(thiophen-2-yl)prop-2-en-1-one (20) and (E)-2-((1H-indol-2-yl)methylene)cyclopentan-1-one (24) displayed high anti-tubercular activity at 50 µg/ml with MIC values of 210, 197 and 236 µM respectively. The in-silico studies revealed that compound 18 exhibit binding modes similar to FAS-II inhibitors like INH or Thiolactomycin against KasA protein. Cytotoxicity assay results suggest that the compounds 18, 20 and 24 are non-cytotoxic to human megakaryocytes and murine B cells.

Tumor microenvironment-responsive polydopamine-based core/shell nanoplatform for synergetic theranostics.

Theranostic agents that integrate diagnostic and therapeutic modalities have drawn extensive attention due to their ability to deliver real-time imaging-guided tumor treatment. Herein, a novel core-shell polydopamine (PDA)-based theranostic agent (PDA@TA-Fe) was fabricated via a two-step strategy. Upon 808 nm and 1064 nm laser irradiation, this agent exhibited high photothermal conversion efficiencies of 29% and 41%, respectively. After endocytosis into tumor cells, the TA-Fe shell of PDA@TA-Fe gradually disintegrated in the weakly acidic tumor microenvironment (TME), and released the TA as an acidity-activated reductant that could reduce Fe3+ to Fe2+. Subsequently, the generated Fe2+ reacted with H2O2 to generate toxic hydroxyl radicals (˙OH) via the Fenton reaction, which induced the apoptosis of tumor cells and achieved the chemodynamic therapy (CDT). The heat produced by photothermal therapy (PTT) accelerated the ˙OH generation to achieve a synergetic effect of CDT/PTT. In vivo tumor-xenograft imaging and therapeutic assays demonstrated obvious contrast enhancement at the tumor site in the T1/T2-weighted MR imaging and efficient tumor suppression achieved after the intravenous injection of this agent because of the enhanced permeation and retention (EPR) effect. This study offered a new strategy to design an "all-in-one" nanoplatform for T1/T2 MR imaging-guided synergistic cancer treatment of CDT/PTT.

Sensitive and reliable electrochemical detection of nitrite and H2O2 embellish-CoPc coupled with appliance of composite MWCNTs.

The electrocatalytic properties of tetra L-Methionine cobalt (II) phthalocyanine (CoTL-MethPc) and functionalized MWCNTs, decorated on glassy carbon electrode (GCE) was investigated. The synthesis of the CoTL-MethPc was confirmed using UV-Vis, FT-IR, XRD, TGA and MASS techniques. Successful modification of GCE with the CoTL-MethPc and their composite was also confirmed using cyclic voltammetry (CVs), differential pulse voltammetry (DPV) and chrono-amperometry (CA) techniques. CoTL-MethPc/MWCNTs/GCE was the best electrode towards nitrite and hydrogen peroxide (H2O2) detection with a very low detection limit (30 and 10 nmol L-1) by CVs method, which compared favorably with literature, good sensitivity, electrocatalytic oxidation of nitrite and hydrogen peroxide on CoTL-MethPc/MWCNTs/GCE electrode was diffusion controlled but characterized with some adsorption of electro-oxidation-reduction reaction intermediates products. The fabricated sensors are easy to prepare, cost-effective and can be applied for real sample analysis of nitrite in beetroot vegetable. The excellent electrocatalytic property of CoTL-MethPc/MWCNTs is high reproducibility, repeatability, selectivity.

Discovery, synthesis, and optimization of an N-alkoxy indolylacetamide against HIV-1 carrying NNRTI-resistant mutations from the Isatis indigotica root.

From an aqueous decoction of the traditional Chinese medicine "ban lan gen" (the Isatis indigotica root), an antiviral natural product CI - 39 was isolated as an NNRTI (non-nucleoside reverse transcriptase inhibitor) (EC50 = 3.40 µM). Its novel structure was determined as methyl (1-methoxy-1H-indol-3-yl)acetamidobenzoate by spectroscopic data and confirmed by single crystal X-ray diffraction. Through synthesis and structure-activity relationship (SAR) investigation of CI - 39 and 57 new derivatives (24 with EC50 values of 0.06-8.55 µM), two optimized derivatives 10f and 10i (EC50: 0.06 µM and 0.06 µM) having activity comparable to that of NVP (EC50 = 0.03 µM) were obtained. Further evaluation verified that 10f and 10i were RT DNA polymerase inhibitors and exhibited better activities and drug resistance folds compared to NVP against seven NNRTI-resistant strains carrying different mutations. Especially, 10i (EC50 = 0.43 µM) was more active to the L100I/K103N double-mutant strain as compared to both NVP (EC50 = 0.76 µM) and EFV (EC50 = 1.08 µM). The molecular docking demonstrated a possible binding pattern between 10i and RT and revealed activity mechanism of 10i against the NNRTI-resistant strains.

An Optical/Photoacoustic Dual-Modality Probe: Ratiometric in/ex Vivo Imaging for Stimulated H2S Upregulation in Mice.

Tracking signaling H2S in live mice demands responsive imaging with fine tissue imaging depth and low interferences from tissue scattering/autofluorescence and probe concentration. With complementary advantages of fluorescence and photoacoustic (PA) imaging, optical/PA dual-modality imaging was suggested for in/ex vivo H2S imaging. Therefore, a meso-benzoyloxyltricarboheptamethine cyanine, HS-CyBz, was prepared as the first ratiometric optical/PA dual-modality probe for H2S, profiting from a keto-enol transition sensing mechanism. Tail intravenous injection of this probe leads to probe accumulation in the liver of mice, and the endogenous H2S upregulation triggered by S-adenosyl-l-methionine has been verified by ratiometric optical/PA imaging, suggesting the promising potential of this ratiometric dual-modality imaging.

Design, Synthesis, and Biological Evaluation of Substituted 4,6-Dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3'-indoline]-2',5(3H)-dione Analogues as Potent NS4B Inhibitors for the Treatment of Dengue Virus Infection.

A series of substituted 4,6-dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3'-indoline]-2',5(3H)-dione analogues were synthesized and evaluated as potent dengue virus inhibitors. Throughout a structure-activity relationship exploration on the amide of the indolone moiety, a wide range of substitutions were found to be well tolerated for chemical optimization at this position. Among these compounds, 15 (JMX0254) displayed the most potent and broad inhibitory activities, effective against DENV-1 to -3 with EC50 values of 0.78, 0.16, and 0.035 µM, respectively, while compounds 16, 21, 27-29, 47, and 70 exhibited relatively moderate to high activities with low micromolar to nanomolar potency against all four serotypes. The biotinylated compound 73 enriched NS4B protein from cell lysates in pull-down studies, and the findings together with the mutation investigations further validated dengue NS4B protein as the target of this class of compounds. More importantly, compound 15 exhibited good in vivo pharmacokinetic properties and efficacy in the A129 mouse model, indicating its therapeutic potential against the dengue virus infection as a drug candidate for further preclinical development.

Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis.

Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD+.

[Synthesis and antitumor activity of novel indole podophyllotoxin derivatives].

According to drug design flattening principle,a series of novel indole podophyllotoxin derivatives which were introduced different indole substituents in C-4 position on the basis of podophyllotoxin nucleus were synthesized with the starting material podophyllotoxin and 1 H-indole-5-carboxylic acid. Its anti-tumor activity in vitro was tested in order to screen for high-efficiency and low-toxic compounds. Six target compounds were synthesized,and were confirmed by~1 H-NMR,~(13)C-NMR,HR-ESI-MS and melting point determination analysis. All these target compounds were not reported by previous literature. Using etoposide as positive control drug,all the target compounds were screened for cytotoxicity against He La cells,K562 cells and K562/A02 cell in vitro by MTT method. The antitumor activity screening results showed that compounds 4 b,4 e,4 f exhibited higher inhibitory rate against He La cells and K562 cells than those of control drug VP-16. This route has the advantages on simple operation and reasonable design,provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.

An anti-inflammatory nanoagent for tumor-targeted photothermal therapy.

We developed an anti-inflammatory nanoagent by combining polydopamine nanospheres with aspirin and cancer cell membrane coating, which can effectively kill cancer cells and simultaneously eliminate photothermal therapy-induced inflammation.

Bioinspired Polydopamine/Polyzwitterion Coatings for Underwater Anti-Oil and -Freezing Surfaces.

Zwitterionic polymers are continually suggested as promising alternatives to tune the surface/interface properties of materials in many fields because of their unique molecular structures. Tremendous efforts have been devoted to immobilizing zwitterionic polymers (polyzwitterions, PZIs) on the material surfaces. However, these efforts usually suffer from cumbersome and time-consuming procedures. Herein we report a one-step strategy to facilely achieve the bioinspired polydopamine/polyzwitterion (PDA/PZI) coatings on various substrates. It requires only 30 min to form PDA/PZI coatings by mixing oxidant, dopamine, and zwitterionic monomers, including carboxybetaine methacrylate (CBMA), sulfobetaine methacrylate (SBMA), and 2-methacryloxyethyl phosphorylcholine (MPC). These bioinspired coatings display multifunctional properties such as underwater antioil-adhesion and antifreezing thanks to their high hydrophilicity and underwater superoleophobicity. The coatings even show the antiadhesion property for crude oil with high viscosity. Therefore, the PDA/PZI-coated meshes are efficient for separating both light oil and crude oil from oil/water mixtures. All these results demonstrate that the one-step strategy is a facile approach to design and exploit the bioinspired PDA/PZI coatings for diverse applications.

An efficient synthesis and biological evaluation of novel analogues of natural product Cephalandole A: A new class of antimicrobial and antiplatelet agents.

Cephalandole A 2, a small indole alkaloid isolated from the Taiwanese orchid Cephalanceropsis gracilis (Orchidaceae), exhibits anticancer activity. Surprisingly, this natural product has not been evaluated for any other biological activity so far. To discover other novel potential of Cephalandole A 2, an efficient and economic synthetic protocol for novel Cephalandole A analogues 21a-o has been developed, in only 3 steps from using indole, and applied for their biological activity. Biological testing showed that Cephalandole A 2 and its novel analogues 21a-o exhibited potential antimicrobial and antiplatelet activity in preliminary assay. To the best of our knowledge, this is the first report of Cephalandole A 2 and its novel synthetic analogues 21a-o as a new class of antimicrobial and antiplatelet agents. In this study, 2 and other analogues i.e., 21b, 21d, 21i and 21o showed promising antimicrobial activity against the phytopathogenic bacteria and fungi. Cephalandole A 2, 21c, 21f and 21i, also showed potent antiplatelet activity.

Phthalocyanine-Assembled Nanodots as Photosensitizers for Highly Efficient Type†I Photoreactions in Photodynamic Therapy.

Owing to their unique, nanoscale related optical properties, nanostructures assembled from molecular photosensitizers (PSs) have interesting applications in phototheranostics. However, most nanostructured PS assemblies are super-quenched, thus, preventing their use in photodynamic therapy (PDT). Although some of these materials undergo stimuli-responsive disassembly, which leads to partial recovery of PDT activity, their therapeutic potentials are unsatisfactory owing to a limited ability to promote generation reactive oxygen species (ROS), especially via type I photoreactions (i.e., not by 1 O2 generation). Herein we demonstrate that a new, nanostructured phthalocyanine assembly, NanoPcA, has the ability to promote highly efficient ROS generation via the type I mechanism. The results of antibacterial studies demonstrate that NanoPcA has potential PDT applications.